Acute myocardial infarction (AMI) continues to be a leading cause of death and disability in the United States. Early detection of AMI is critical for making appropriate therapeutic and triage decisions. Assays which measure increased activity of various serum enzymes have played an important role in detecting AMI. Even so, acute chest pain remains a difficult diagnostic problem as autopsy results indicate many myocardial infarctions go undetected (Lee et al., Ann. Int. Med. 105:221-233, 1986).
The pathophysiologic basis of acute myocardial ischemia (unstable angina pectoris and AMI) has been clearly defined over the past decade. Acute myocardial ischemia is generally thought to be the result of an occlusive thrombus in the atherosclerotic coronary artery. The myocardium may recover from a brief period of ischemia due to a transient and intermittent reduction in coronary blood flow. When the reduction in coronary blood flow is persistent and prolonged, however, an acute myocardial infarction may occur (Mehta, et al., JACC, 15:727-729, 1990).
It is now believed that both unstable angina pectoris (UAP) and AMI are parts of the same pathologic spectrum involving extensive endothelial disruption, activation of platelets at the site of endothelial disruption, and enlargement of the thrombus by incorporation of fibrin and other cellular elements. It is likely that the thrombus is unstable in patients with unstable angina pectoris and stable and firm in patients who develop myocardial necrosis.
Platelets play a central role in hemostasis and in the genesis of arterial thrombosis. Arterial thrombi are composed mainly of aggregated platelets but are also rich in granulocytes (see e.g., Levine, et al., Jor. Clin. Invest. 57: 955-963, 1976). Both monocytes and platelets are known to contribute to myocardial damage following ischemia (Entman et al., FASEB J, 5:2529-2537, 1991; Folts et al., Circulation 54: 365-370, 1976; Yee et al., J. Surg. Res. 40:499-503, 1986).
Coronary endothelial damage and platelet activation are believed to be the pathophysiologic basis of coronary artery occlusion. Activated platelets release potent spasmogens and platelet aggregants, such as thromboxane A2 and serotonin, that exert a vasoconstrictive influence either at the site of thrombus or downstream, beyond the site of arterial occlusion (Mehta, J., JACC 15: 727-729, 1990).
Platelet activation is also associated with surface expression of the .alpha.-granule external membrane protein-140 (GMP-140), designated CD62 and also known as platelet activation-dependent granule external membrane protein (PADGEM) or P-selectin. GMP-140 mediates platelet adhesion to polymorphonuclear leucocytes (PMN) and monocytes (Larsen et al., Cell, 59:305, 1989).
Recently, a flow cytometric assay that accurately quantifies platelet-leukocyte adhesion has been developed. The assay accurately measures the percentage of leukocytes binding platelets and the relative number of platelets bound per cell (Rinder et al., Blood, 78:1760-1769, 1991). Using this assay, Rinder et al. have shown that platelet activation on cardiopulmonary bypass (CPB) is temporally accompanied by increased monocyte and PMN adhesion to platelets (Rinder et al., Blood, 79:1201-1205).
AMI has been clinically defined by the World Health Organization (WHO criteria for the diagnosis of acute myocardial infarction; Geneva:Cardiovascular Diseases Unit, 1981). Under the WHO criteria, any two of the following are used for a diagnosis of AMI: (a) typical chest pain, (b) a new Q wave on ECG, and (c) peak enzymes (CK, SCOT or LDH) exceeding two times the upper normal value.
It should be noted, however, that the presence of a new Q wave is rare. Evolution of Q wave abnormalities appear approximately four to eight hours post AMI. Diagnosis of AMI is generally made on chest pain and non-diagnostic changes in the ECG. Typical chest pain is chest pain which radiates down the left arm and into the left hand with a tingling sensation in the fingers.
The cytosolic isoenzyme CK-MB is standard clinical laboratory test used in diagnosing AMI. The serum enzyme creatine kinase (CK) has two subunits, that differ in amino acid sequence and tissue specificity. CK-MB was initially believed to be found only in myocardial cells but more sensitive assays have revealed trace amounts of its presence in other tissues such as normal skeletal muscle. Although increases in CK-MB can occur from non-cardiac sources such as surgery and trauma, elevation in CK-MB in the absence of these factors is highly correlated with myocardial ischemia. (Lee, et al., Ann. Int. Med. 105: 221-223, 1986).
The traditional CK-MB assay requires serial sampling on admission and about twelve and twenty four hours later (Saxena, et al., Arch. Pathol. Lab. Med. 117:180-183). This poses a diagnostic dilemma for emergency physicians because thrombolytic therapy must be initiated within four to six hours after infarction. Because the sensitivity of a single CK-MB determination is low (34%), a single test cannot be used to exclude a diagnosis of AMI. In addition, there may be a significant delay in obtaining the results of CK-MB prior to initiating thrombolytic therapy.
Although it has been suggested that the traditional twenty four hour CK-MB sampling be replaced with two or three very early measurements over a six hour period (Apple et al., Clin. Chem. 37:909, 1991), the time interval between onset of symptoms and appearance of serum CK-MB in clinically significant range varies from 2.8 to 15.1 hours (Irvin et al., Arch. Intern. Med. 140:329-334, 1980). Thus, CK-MB levels determined during the early hours after the onset of symptoms may be negative in a patient who actually has an AMI.
The need for rapid and analytically sensitive assays to replace CK-MB has been an area of great research interest. Many alternatives have been described including assays of CK isoforms (Puelo et al., Clin. Chem. 35:1452-1455, 1989), myoglobin (Drexel et al., Am. Heart J. 105:642-650, 1983), and troponin isoenzymes (Katus et al., J. Mol. Cell Cardiol. 21:1349-1353, 1989). These assays are also based on the appearance of a serum marker of cardiac muscle damage. Similar to the CK-MB assay, the assays must be performed on admission and about twelve and twenty four hours later for a reliable reading. In addition, assay results have at least a one hour turn-around time.
Because of the very different treatment regimes called for in UAP and AMI, early detection of AMI remains an important goal of emergency room care. Thrombolytic therapy is beneficial in AMI if instituted within four to six hours after infarction. It is not beneficial in UAP. Furthermore, thrombolytic therapy is associated with significant risk, e.g., hemorrhage.
It has become apparent that the WHO criteria are nonspecific and do not distinguish transient myocardial ischemia from necrosis. One study has shown that of those patients hospitalized with suspected acute necrosis, only 30% were subsequently confirmed to have AMI (see e.g., Puelo et al., Circulation, 82:759-764 1990).
In addition, more than 50% of the deaths associated with AMI occur within the first two hours after the onset of symptoms of coronary ischemia (Apple, F.S., A.J.C.P.97: 217-226, 1990). Certainly, diagnosis of AMI by CK-MB assay cannot be relied upon during this brief time frame.
Finally, the finding that physicians fail to diagnose myocardial infarctions with alarming frequency (Lee et al., Ann. Int. Med., 105: 221-233) highlights the severe shortcomings still associated with the present state of the art.
Thus, the need is great for a quick and accurate means of identifying an AMI patient from among those patients exhibiting symptoms suggestive of ischemic heart disease.